Our understanding of the physiology and biochemistry of acid-base and fluid-electrolyte regulations has greatly expanded in recent years. Key physiologic principles have emerged that now permit rational diagnosis and therapy of clinical disorders of serum electrolyte concentration. This paper describes diagnostic strategies based upon these principles. The etiology of the myriad factors in hyponatremia is best derived by first measuring serum tonicity and then assessing extracellular fluid volume. The hyper-, iso- and hypotonic hyponatremia are defined, and the hypotonic group is subclassified into hypo-, iso- and hyper volemic forms. The hypernatremias are best categorized by their state of volume expansion. Classification into the hypo-, hyper- and isovolemic hypernatremias simplifies their diagnosis. Metabolic acidoses are classified in terms of the anion gap. Clinical and chemical aspects of increased and normal anion gap acidoses are described. Metabolic alkaloses require a source of new bicarbonate and its retention by the kidney. The means by which new alkali is synthesized and urinary loss prevented serve to effectively classify the alkaloses. Hypokalemic syndromes are defined in terms of associated changes in body potassium. The potassium-depleted states are further subclassified by whether normotension or hypertension is associated. Hyperkalemia is produced by redistribution of cellular and extracellular potassium or by increased body potassium. Defects in the renin-angiotensin-aldosterone-distal renal tubule effector arm usually underlie hyperkalemic states, which are than classified in terms of this regulatory hormonal cascade. Classifications for disordered serum concentrations of calcium, magnesium, phosphorus and uric acid are presented. Hormonal, metabolic and renal regulatory factors form the basis for an organized approach to these disorders.